The effect of CTCA guided selective invasive graft assessment on coronary angiographic parameters and outcomes: Insights from the BYPASS-CTCA trial.

BACKGROUND: Computed tomography cardiac angiography (CTCA) is recommended for the evaluation of patients with prior coronary artery bypass graft (CABG) surgery. The BYPASS-CTCA study demonstrated that CTCA prior to invasive coronary angiography (ICA) in CABG patients leads to significant reductions in procedure time and contrast-induced nephropathy (CIN), alongside improved patient satisfaction. However, whether CTCA information was used to facilitate selective graft cannulation at ICA was not protocol mandated. In this post-hoc analysis we investigated the influence of CTCA facilitated selective graft assessment on angiographic parameters and study endpoints. METHODS: BYPASS-CTCA was a randomized controlled trial in which patients with previous CABG referred for ICA were randomized to undergo CTCA prior to ICA, or ICA alone. In this post-hoc analysis we assessed the impact of selective ICA (grafts not invasively cannulated based on the CTCA result) following CTCA versus non-selective ICA (imaging all grafts irrespective of CTCA findings). The primary endpoints were ICA procedural duration, incidence of CIN, and patient satisfaction post-ICA. Secondary endpoints included the incidence of procedural complications and 1-year major adverse cardiac events. RESULTS: In the CTCA cohort (n â€‹= â€‹343), 214 (62.4%) patients had selective coronary angiography performed, whereas 129 (37.6%) patients had non-selective ICA. Procedure times were significantly reduced in the selective CTCA â€‹+ â€‹ICA group compared to the non-selective CTCA â€‹+ â€‹ICA group (-5.82min, 95% CI -7.99 to -3.65, p â€‹< â€‹0.001) along with reduction of CIN (1.5% vs 5.8%, OR 0.26, 95% CI 0.10 to 0.98). No difference was seen in patient satisfaction with the ICA, however procedural complications (0.9% vs 4.7%, OR 0.21, 95% CI 0.09-0.87) and 1-year major adverse cardiac events (13.1% vs 20.9%, HR 0.55, 95% CI 0.32-0.96) were significantly lower in the selective group. CONCLUSIONS: In patients with prior CABG, CTCA guided selective angiographic assessment of bypass grafts is associated with improved procedural parameters, lower complication rates and better 12-month outcomes. Taken in addition to the main findings of the BYPASS-CTCA trial, these results suggest a synergistic approach between CTCA and ICA should be considered in this patient group. REGISTRATION: ClinicalTrials.gov, NCT03736018.

Intravascular imaging assessment of pharmacotherapies targeting atherosclerosis: advantages and limitations in predicting their prognostic implications.

Intravascular imaging has been often used over the recent years to examine the efficacy of emerging therapies targeting plaque evolution. Serial intravascular ultrasound, optical coherence tomography, or near-infrared spectroscopy-intravascular ultrasound studies have allowed us to evaluate the effects of different therapies on plaque burden and morphology, providing unique mechanistic insights about the mode of action of these treatments. Plaque burden reduction, a decrease in necrotic core component or macrophage accumulation-which has been associated with inflammation-and an increase in fibrous cap thickness over fibroatheromas have been used as surrogate endpoints to assess the value of several drugs in inhibiting plaque evolution and improving clinical outcomes. However, some reports have demonstrated weak associations between the effects of novel treatments on coronary atheroma and composition and their prognostic implications. This review examines the value of invasive imaging in assessing pharmacotherapies targeting atherosclerosis. It summarizes the findings of serial intravascular imaging studies assessing the effects of different drugs on atheroma burden and morphology and compares them with the results of large-scale trials evaluating their impact on clinical outcome. Furthermore, it highlights the limited efficacy of established intravascular imaging surrogate endpoints in predicting the prognostic value of these pharmacotherapies and introduces alternative imaging endpoints based on multimodality/hybrid intravascular imaging that may enable more accurate assessment of the athero-protective and prognostic effects of emerging therapies.

Rapid Assessment and Treatment In Decompensated Aortic Stenosis (ASTRID-AS study)- A pilot study.

BACKGROUND: Acute decompensated aortic stenosis (ADAS) is common and associated with higher mortality, acute kidney injury (AKI) and longer hospital length of stay (LoS) compared with electively treated stable AS. The aim of this study was to assess the impact of a dedicated pathway that reduces time to transcatheter aortic valve implantation (TAVI) in ADAS, hypothesizing that LoS can be reduced without compromising patient safety. METHODS AND RESULTS: Using a prospective, open label, cluster design, patients from 5 referring centres were allocated to the ASessment and TReatment In Decompensated Aortic Stenosis (ASTRID-AS) pathway where the diagnosis, referral, investigations and treatment of ADAS were prioritised and expedited. 15 hospitals remained on the conventional pathway that followed the same process, albeit according to a waiting list. The primary efficacy endpoint was hospital LoS and the secondary safety endpoint, a composite of death or AKI at 30 days post-TAVI. 58 conventional patients and 25 ASTRID-AS patients were included in this study. Time to TAVI in the conventional vs. ASTRID-AS cohort was 22 (15-30) vs. 10 (6-12) days; P < 0.001, respectively. Length of hospital stay was 24 (18-33) vs. 13 (8-18) days; P < 0.001, respectively. 13.4 bed days were saved per patient using the ASTRID-AS pathway. Secondary safety endpoint occurred in 12 (20.7%) vs. 1 (4.0%) patients; P = 0.093, respectively. Procedural complications were similar between the two cohorts. CONCLUSION: A dedicated pathway for ADAS that shortens time to TAVI demonstrated reduced hospital LoS without compromising patient safety and a trend towards improving clinical outcomes.

NITRATE-CIN Study: Protocol of a Randomized (1:1) Single-Center, UK, Double-Blind Placebo-Controlled Trial Testing the Effect of Inorganic Nitrate on Contrast-Induced Nephropathy in Patients Undergoing Coronary Angiography for Acute Coronary Syndromes.

BACKGROUND: Contrast-induced nephropathy (CIN), an acute kidney injury resulting from the administration of intravascular iodinated contrast media, is a significant cause of morbidity/mortality following coronary angiographic procedures in high-risk patients. Despite preventative measures intended to mitigate the risk of CIN, there remains a need for novel effective treatments. Evidence suggests that delivery of nitric oxide (NO) through chemical reduction of inorganic nitrate to NO may offer a novel therapeutic strategy to reduce CIN and thus preserve long term renal function. DESIGN: The NITRATE-CIN trial is a single-center, randomized, double-blind placebo-controlled trial, which plans to recruit 640 patients presenting with acute coronary syndromes (ACS) who are at risk of CIN. Patients will be randomized to either inorganic nitrate therapy (capsules containing 12 mmol KNO3) or placebo capsules containing potassium chloride (KCl) daily for 5 days. The primary endpoint is development of CIN using the Kidney Disease Improving Global Outcomes (KDIGO) criteria. A key secondary endpoint is renal function over a 3-month follow-up period. Additional secondary endpoints include serum renal biomarkers (e.g. neutrophil gelatinase-associated lipocalin) at 6 h, 48 h and 3 months following administration of contrast. Cost-effectiveness of inorganic nitrate therapy will also be evaluated. SUMMARY: This study is designed to investigate the hypothesis that inorganic nitrate treatment decreases the rate of CIN as part of semi-emergent coronary angiography for ACS. Inorganic nitrate is a simple and easy to administer intervention that may prove useful in prevention of CIN in at-risk patients undergoing coronary angiographic procedures.

Iatrogenic catheter-induced ostial coronary artery dissections: Prevalence, management, and mortality from a cohort of 55,968 patients over 10 years.

OBJECTIVE: We sought to describe the prevalence, management strategies and evaluate the prognosis of patients with iatrogenic catheter-induced ostial coronary artery dissection (ICOCAD). BACKGROUND: ICOCAD is a rare but potentially devastating complication of cardiac catheterisation. The clinical manifestations of ICOCAD vary from asymptomatic angiographic findings to abrupt vessel closure leading to myocardial infarction and death. METHODS: 55,968 patients who underwent coronary angiography over a 10-year period were screened for ICOCAD as defined by the National Heart, Lung, and Blood Institute. The management and all-cause mortality were retrieved from local and national databases. RESULTS: The overall prevalence of ICOCAD was 0.09% (51/55,968 patients). Guide catheters accounted for 75% (n = 37) of cases. Half of the ICOCAD cases involved the right coronary artery while the remaining were related to left main stem (23/51; 45%) and left internal mammary artery (2/51; 4%). Two-thirds of ICOCAD were high grade (type D, E, and F). The majority of cases were type F dissections (n = 18; 66%), of which two third occurred in females in their 60s. The majority of ICOCAD patients (42/51; 82%) were treated with percutaneous coronary intervention while the remaining underwent coronary artery bypass grafting (3/51; 6%) or managed conservatively (6/51; 12%). Three deaths occurred during the index admission while 48/51 patients (94.1%) were safely discharged without further mortality over a median follow-up of 3.6 years. CONCLUSIONS: ICOCAD is a rare but life-threatening complication of coronary angiography. Timely recognition and prompt bailout PCI is a safe option for majority of patients with good clinical outcomes.

Computerised Methodologies for Non-Invasive Angiography-Derived Fractional Flow Reserve Assessment: A Critical Review.

Fractional flow reserve is the gold standard for assessing the haemodynamic significance of intermediate coronary artery stenoses. Cumulative evidence has shown that FFR-guided revascularisation reduces stent implantations and improves patient outcomes. However, despite the wealth of evidence and guideline recommendations, its use in clinical practice remains minimal. Patient and technical limitations of FFR as well as the need for intracoronary instrumentation, use of adenosine, and increased costs have limited FFR's applicability in clinical practice. Over the last decade, several angiography-derived FFR software packages have been developed which do not require intracoronary pressure assessment with a guidewire or need for administration of hyperaemic agents. At present, there are 3 commercially available software packages and several other non-commercial technologies that have been described in the literature. These technologies have been validated against invasive FFR showing good accuracy and correlation. However, the methodology behind these solutions is different-some algorithms are based on solving the governing equations of fluid dynamics such as the Navier-Stokes equation while others have opted for a more simplified mathematical formula approach. The aim of this review is to critically appraise the methodology behind all the known angiography-derived FFR technologies highlighting the key differences and limitations.

Application of the DILEMMA score to improve lesion selection for invasive physiological assessment.

OBJECTIVES: We sought to assess the validity of the DILEMMA score against instantaneous wave-free ratio (iFR) and evaluate its utility in rationalizing the number of patients referred for invasive physiological assessment. BACKGROUND: The DILEMMA score is a validated angiographic scoring tool incorporating minimal lumen diameter, lesion length and subtended myocardial area that has been shown to predict the functional significance of lesions as assessed by fractional flow reserve (FFR). METHODS: Patients in the DEFINE-FLAIR study who had coronary stenosis of intermediate severity were randomized to either FFR or iFR. DILEMMA score was calculated retrospectively on a subset of this cohort by operators blinded to FFR or iFR values. RESULTS: Three hundred and forty-six lesions (181 assessed by FFR; 165 by iFR) from 259 patients (mean age 66.0 years, 79% male) were included. A DILEMMA score ≤ 2 had a negative predictive value of 96.3% and 95.7% for identifying lesions with FFR >0.80 and iFR >0.89, respectively. A DILEMMA score ≥ 9 had a positive predictive value of 88.9% and 100% for identifying lesions with FFR ≤0.80 and iFR ≤0.89, respectively. The receiver operating characteristic area under the curve values for DILEMMA score to predict FFR ≤0.80 and iFR ≤0.89 were 0.83 (95% CI 0.77-0.90) and 0.82 (0.75-0.89) respectively. A DILEMMA score ≤ 2 or ≥9 occurred in 172 of the 346 lesions (49.7%). CONCLUSIONS: Using DILEMMA score in patients with coronary stenosis of intermediate severity may reduce the need for pressure wire use, offering potential cost-savings and minimizing the risks associated with invasive physiological lesion assessment.

Sodium Nitrite-Mediated Cardioprotection in Primary Percutaneous Coronary Intervention for ST-Segment Elevation Myocardial Infarction: A Cost-Effectiveness Analysis.

OBJECTIVES: In the follow-up of patients in a trial of intracoronary sodium nitrite given during primary percutaneous coronary intervention (PCI) after acute myocardial infarction (AMI), we found a reduction in the incidence of major adverse cardiac events (MACEs). Specifically, MACE rates were 5.2% versus 25.0% with placebo at 3 years ( P = .013). Such MACE reductions should also be associated with economic benefit. Thus, we assessed the cost utility of sodium nitrite therapy versus standard primary PCI only. METHODS AND RESULTS: We developed a model to simulate costs and quality-adjusted life years (QALYs) over the first 36 months after ST-Segment Elevation Myocardial Infarction (STEMI). Decision tree analysis was used to assess different potential cardiovascular outcomes after STEMI for patients in both treatment groups. Model inputs were derived from the NITRITE-AMI study. Cost of comparative treatments and follow-up in relation to cardiovascular events was calculated from the United Kingdom National Health Service perspective. Higher procedural costs for nitrite treatment were offset by lower costs for repeat revascularization, myocardial infarction, and hospitalization for heart failure compared to primary PCI plus placebo. Nitrite treatment was associated with higher utility values (0.91 ± 0.19 vs 0.82 ± 0.30, P = .041). The calculated incremental cost-effectiveness ratio of £2177 per QALY indicates a cost-effective strategy. Furthermore, positive results were maintained when input parameters varied, indicating the robustness of our model. In fact, based on the difference in utility values, the cost of nitrite could increase by 4-fold (£2006 per vial) and remain cost-effective. CONCLUSION: This first analysis of sodium nitrite as a cardioprotective treatment demonstrates cost-effectiveness. Although more comparative analysis and assessment of longer follow-up times are required, our data indicate the considerable potential of nitrite-mediated cardioprotection.

The effect of intracoronary sodium nitrite on the burden of ventricular arrhythmias following primary percutaneous coronary intervention for acute myocardial infarction.

OBJECTIVE: Pre-clinical evidence suggests delivery of nitric oxide (NO) through administration of inorganic nitrite suppresses arrhythmias resulting from acute ischaemia and reperfusion (I/R). To date no assessment of whether inorganic nitrite might limit reperfusion arrhythmia has occurred in man, therefore we explored the effects on I/R-induced ventricular arrhythmias in the NITRITE-AMI cohort. METHODS: In the NITRITE-AMI cohort, Holter analysis was performed prior to and for 24 h after primary PCI in 80 patients who received either intra-coronary sodium nitrite (N = 40) or placebo (N = 40) during primary PCI for AMI. RESULTS: Ventricular rhythm disturbance was experienced by 100% patients; however, there was no difference in the number between the groups, p = .2196. Non-sustained ventricular tachycardia (NSVT) occurred in 67.5% (27/40) of nitrite-treated patients compared to 89% (35/39) of those treated with placebo (p = .027). There was a significant reduction in both the number of runs (63%, p ≤.0001) and total beats of NSVT (64%, p = .0019) in the nitrite-treated patients compared to placebo. Post-hoc analyses demonstrate a direct correlation of occurrence of NSVT with infarct size, with the correlation stronger in the placebo versus the nitrite group initiating an independent nitrite effect (Nitrite: r = 0.110, p = .499, placebo: r = 0.527, p = .001, p for comparison: 0.004). CONCLUSION: Overall no difference in ventricular rhythm disturbance was seen with intra-coronary nitrite treatment during primary PCI in STEMI patients, however nitrite treatment was associated with an important reduction in the incidence and severity of NSVT. In view of the sustained reduction of MACE seen, this effect warrants further study in a large-scale trial.

A quantitative, multi-national and multi-stakeholder assessment of barriers to the adoption of cell therapies.

Cellular therapies, such as stem cell-based treatments, have been widely researched and numerous products and treatments have been developed. Despite this, there has been relatively limited use of these technologies in the healthcare sector. This study sought to investigate the perceived barriers to this more widespread adoption. An anonymous online questionnaire was developed, based on the findings of a pilot study. This was distributed to an audience of clinicians, researchers and commercial experts in 13 countries. The results were analysed for all respondents, and also sub-grouped by geographical region, and by profession of respondents. The results of the study showed that the most significant barrier was manufacturing, with other factors such as efficacy, regulation and cost-effectiveness being identified by the different groups. This study further demonstrates the need for these important issues to be addressed during the development of cellular therapies to enable more widespread adoption of these treatments.

Potential economic consequences of a cardioprotective agent for patients with myocardial infarction: modelling study.

OBJECTIVE: To investigate the cost-effectiveness of a hypothetical cardioprotective agent used to reduce infarct size in patients undergoing percutaneous coronary intervention (PCI) after anterior ST-elevation myocardial infarction. DESIGN: A cost-utility analysis using a Markov model. SETTING: The National Health Service in the UK. PATIENTS: Patients undergoing PCI after anterior ST-elevation myocardial infarction. INTERVENTIONS: A cardioprotective agent given at the time of reperfusion compared to no cardioprotection. We assumed the cardioprotective agent (given at the time of reperfusion) would reduce the risk and severity of heart failure (HF) after PCI and the risk of mortality after PCI (with a relative risk ranging from 0.6 to 1). The costs of the cardioprotective agent were assumed to be in the range £1000-4000. MAIN OUTCOME MEASURES: The incremental costs per quality-adjusted life-year (QALY) gained, using 95% CIs from 1000 simulations. RESULTS: Incremental costs ranged from £933 to £3820 and incremental QALYs from 0.04 to 0.38. The incremental cost-effectiveness ratio (ICER) ranged from £3311 to £63 480 per QALY gained. The results were highly dependent on the costs of a cardioprotective agent, patient age, and the relative risk of HF after PCI. The ICER was below the willingness-to-pay threshold of £20 000 per QALY gained in 71% of the simulations. CONCLUSIONS: A cardioprotective agent that can reduce the risk of HF and mortality after PCI has a high chance of being cost-effective. This chance depends on the price of the agent, the age of the patient and the relative risk of HF after PCI.

The impact of socio-economic status on all-cause mortality after percutaneous coronary intervention: an observational cohort study of 13,770 patients.

AIMS: The relation between socio-economic status (SES) and outcomes after percutaneous coronary intervention (PCI) has not been established. We sought to determine whether or not socio-economic status impacts on prognosis after PCI. METHODS AND RESULTS: This was an observational cohort study of 13,770 consecutive patients who underwent PCI at a single centre between 2005 and 2011. Patient socio-economic status was defined by the English Index of Multiple Deprivation (IMD) score, according to residential postcode. Patients were analysed by quintile of IMD score (Q1, least deprived; Q5, most deprived). Median follow-up was 3.7 (IQR: 2.0-5.1) years and the primary outcome was all-cause mortality. Patients in Q5 (most deprived) were younger, more commonly South Asian, and had higher rates of smoking, diabetes mellitus, renal impairment, previous MI, and previous PCI than patients in Q1. Rates of long-term mortality increased progressively across the five quintiles of IMD score in a linear fashion (p=0.0004), as did rates of recurrent MI, target vessel revascularisation, and CABG. The difference in mortality rates persisted after adjustment for other potential confounding factors after multivariate analysis (Q5 vs. Q1: HR 1.93, 95% CI: 1.38-2.69). CONCLUSIONS: In this large contemporary cohort of patients receiving PCI, socio-economic status was associated with prognosis in a linear fashion.

Quantitative assessment of barriers to the clinical development and adoption of cellular therapies: A pilot study.

There has been a large increase in basic science activity in cell therapy and a growing portfolio of cell therapy trials. However, the number of industry products available for widespread clinical use does not match this magnitude of activity. We hypothesize that the paucity of engagement with the clinical community is a key contributor to the lack of commercially successful cell therapy products. To investigate this, we launched a pilot study to survey clinicians from five specialities and to determine what they believe to be the most significant barriers to cellular therapy clinical development and adoption. Our study shows that the main concerns among this group are cost-effectiveness, efficacy, reimbursement, and regulation. Addressing these concerns can best be achieved by ensuring that future clinical trials are conducted to adequately answer the questions of both regulators and the broader clinical community.